Inflammation is a complex process in which the body's defense system combats foreign entities. While the battle against foreign entities may be necessary for the body's survival, some defense systems respond to foreign entities, even innocuous ones, as dangerous and thereby damage surrounding tissue in the ensuing conflict.
Atopic allergy or atopy, is an ecogenetic disorder, where genetic background dictates the response to environmental stimuli, such as pollen, food, dander and insect venoms. The disorder is generally characterized by an increased ability of lymphocytes to produce IgE antibodies in response to ubiquitous antigens. Activation of the immune system by these antigens leads to allergic inflammation and may occur after ingestion, penetration through the skin or after inhalation. When this immune activation occurs and is accompanied by pulmonary inflammation and bronchial hyperresponsiveness, this disorder is broadly characterized as asthma. Many cell types are involved in this inflammatory reaction and they include T cells and antigen-presenting cells, B cells that produce IgE and basophils and eosinophils that bind IgE. These inflammatory cells accumulate at the site of allergic inflammation and the toxic products they release contribute to tissue destruction related to these disorders.
While asthma is generally defined as an inflammatory disorder of the airways, clinical symptoms arise from intermittent air flow obstruction. It is a chronic, disabling disorder that appears to be increasing in prevalence and severity (Gergen et al., (1992) Am. Rev. Respir. Dis. 146, 823–824). It is estimated that 30–40% of the population suffer with atopic allergy and 15% of children and 5% of adults in the population suffer from asthma (Gergen et al., (1992) Am. Rev. Respir. Dis. 146, 823–824). Thus, an enormous burden is placed on our health-care resources.
Interestingly, while most individuals experience similar environmental exposures, only certain individuals develop atopic allergy and asthma. This hypersensitivity to environmental allergens known as atopy, is often indicated by elevated serum IgE levels or abnormally intense skin test response to allergens in atopic individuals as compared to non-atopics (Marsh et al., (1982) New Eng. J. Med. 305, 1551–1559). Strong evidence for a close relationship between atopic allergy and asthma is derived from the fact that most asthmatics have clinical and serologic evidence of atopy (Clifford et al., (1987) Arch. Dis. Childhood 62, 66–73; Gergen, (1991) Arch. Intern. Med. 151, 487–492; Burrows et al., (1992) J. Allergy Clin. Immunol. 90, 376–385; Johannson et al., (1972) Prog. Clin. Immunol. 1, 1–25; Sears et al., (1991) New Engl. J. Med. 325. 1067–1071; Halonen et al., (1992) Am. Rev. Respir. Dis. 146, 666–670). In particular, younger asthmatics have a high incidence of atopy (Marsh et al., (1982) New Eng. J. Med. 305, 1551–1559). In addition, immunologic factors associated with an increase in total serum IgE levels are very closely related to impaired pulmonary function (Burrows et al., (1989) New Eng. J. Med. 320, 271–277).
Both the diagnosis and treatment of these disorders are problematic (Gergen et al., (1992) Am. Rev. Respir. Dis. 146, 823–824). The assessment of inflamed lung tissue is often difficult and frequently the source of the inflammation cannot be determined. Without knowledge of the source of the airway inflammation and protection from the inciting foreign environmental agent or agents, the inflammatory process cannot be interrupted. It is now generally accepted that failure to control pulmonary inflammation leads to significant loss of lung function over time.
Current treatments suffer from their own set of disadvantages. The main therapeutic agents, beta receptor agonists, reduce the symptoms thereby transiently improving pulmonary function, but do not affect the underlying inflammation so that lung tissue remains in jeopardy. In addition, constant use of beta receptor agonists results in desensitization which reduces their efficacy and safety (Molinoffet al., (1995) Goodman and Gilman's The Pharmacologic Basis of Therapeutics, MacMillan Publishing). The agents that can diminish the underlying inflammation, the anti-inflammatory steroids, have their own list of disadvantages that range from immunosuppression to bone loss (Molinoffet al., (1995) Goodman and Gilman's The Pharmacologic Basis of Therapeutics, MacMillan Publishing).
Because of the problems associated with conventional therapies, alternative treatment strategies have been evaluated. Glycophorin A (Chu et al., (1992) Cell. Immunol. 145, 223–239), cyclosporin (Alexander et al., (1992) Lancet 339, 324–328; Morely, (1992) J. Autoimmun. 5 Suppl A, 265–269) and a nonapeptide fragment of interleukin 2 (IL-2) (Zavyalov et al., (1992) Immunol. Lett. 31, 285–288) all inhibit potentially critical immune functions associated with homeostasis. What is needed in the art is a treatment for asthma that addresses the underlying pathogenesis. Moreover, these therapies should address the episodic nature of the disorder and the close association with allergy and intervene at a point downstream from critical immune functions.
In the related patent applications mentioned above, applicants have demonstrated that interleukin 9 (IL-9), its receptor and activities effected by IL-9 are the appropriate targets for therapeutic intervention in atopic allergy, asthma and related disorders.
Mediator release from mast cells by allergen has long been considered a critical initiating event in allergy. IL-9 was originally identified as a mast cell growth factor and it has been demonstrated that IL-9 up-regulates the expression of mast cell proteases including MCP-1, MCP-2, MCP-4 (Eklund et al., (1993) J. Immunol. 151, 4266–4273) and granzyme B (Louahed et al., (1995) J. Immunol. 154. 5061–5070). Thus, IL-9 appears to serve a role in the proliferation and differentiation of mast cells. Moreover, IL-9 up-regulates the expression of the alpha chain of the high affinity IgE receptor (Dugas et al., (1993) Eur. J. Immunol. 23, 1687–1692). Elevated IgE levels are considered to be a hallmark of atopic allergy and a risk factor for asthma. Furthermore, both in vitro and in vivo studies have shown IL-9 to potentiate the release of IgE from primed B cells (Petit-Frere et al., (1993) Immunology 79, 146–151).
There is substantial support for the role of IL-9 gene in asthma. First, linkage homology between humans and mice suggests that the same gene is responsible for producing biologic variability in response to antigen in both species. Second, differences in expression of the murine IL-9 candidate gene are associated with biologic variability in bronchial responsiveness. In particular, reduced expression of IL-9 is associated with a lower baseline bronchial response in B6 mice (Nicolaides et al., (1997) Proc. Natl. Acad. Sci. USA 94, 13175–13180). Third, recent evidence for linkage disequilibrium in data from humans suggests IL-9 may be associated with atopy and bronchial hyperresponsiveness consistent with a role for this gene in both species (Doull et al., (1996) Am. J. Respir. Crit. Care Med. 153, 1280–1284). Moreover, a genetic alteration in the human gene appears to be associated with loss of cytokine function and lower IgE levels. Fourth, the pleiotropic functions of this cytokine and its receptor in the allergic immune response strongly support a role for the IL-9 pathway in the complex pathogenesis of asthma. Fifth, in humans, biologic variability in the IL-9 receptor also appears to be associated with atopic allergy and asthma. Finally, despite the inherited loss of IL-9 receptor function, these individuals appear to be otherwise healthy. Thus, nature has demonstrated in atopic individuals that the therapeutic down-regulation of IL-9 and IL-9 receptor genes or genes activated by IL-9 and its receptor is likely to be safe.
Airway hyperresponsiveness is found in virtually all asthmatics and in some strains of inbred mice (DBA2) (Levitt et al., (1995) Clin. Exp. Allergy 25, 61–63). Airway hyperresponsiveness is a risk factor for the development of asthma in humans and is used in animal models of asthma as a physiologic measure to assess the efficacy of treatment for asthma. This data along with human (Postma et al., (1995) New Engl. J. Med. 333, 894–900) and murine genetic mapping results (U.S. Pat. No. 5,908,839) suggests a critical role for the murine IL-9 gene product in the airway response of the mouse. In particular, the bronchial hyperresponsive DBA2 mice differ from the C57BL6 hyporesponsive mice (Nicolaides et al., (1997) Proc. Natl. Acad. Sci. USA 94, 13175–13180) in their expression of steady state levels of IL-9 (U.S. Pat. No. 5,908,839). Furthermore, pretreatment with blocking antibodies to IL-9 and its receptor can optionally provide complete protection from antigen induced airway hyperresponsiveness and inflammation in mice demonstrating a critical regulatory role for IL-9 in these immune responses. This data demonstrates that although different molecular changes produce biologic variability in airway responsiveness in humans and mice, these changes arise in the same gene(s) (IL-9 and its receptor) that regulate this pathway. Taken together, these observations confirm the critical role of IL-9 and its receptor in airway hyperresponsiveness, asthma and atopic allergy. Moreover, this data demonstrates that agents of the invention, which block IL-9 action(s), protect against an antigen induced response such as those detailed above.
While the role of the IL-9 gene, its receptor and their functions in atopic allergy, asthma and related disorders has been elucidated, a specific need in the art exists for elucidation of the role of genes which are regulated by IL-9 in the etiology of these disorders. Furthermore, most significantly, based on this knowledge, there is a need for the identification of agents that are capable of regulating the activity of these genes, their gene products and their subsequent biological activities for treating these disorders.